tbuckley/cabot-search huggingface dataset:
DIPG-54. UPDATED FINDINGS FROM THE PHASE IB STUDY OF UNESBULIN (PTC596) IN CHILDREN WITH NEWLY-DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) AND HIGH-GRADE GLIOMA (HGG): A REPORT FROM THE COLLABORATIVE NETWORK FOR NEURO-ONCOLOGY CLINICAL TRIALS (CONNECT)
Authors: Margot Lazow, Patricia Baxter, Joseph Stanek, Diana Rodriguez, Shiva Senthil Kumar, Joshua Palmer, James Leach, Leonie Mikael, Diana Thomas, Christine Fuller, Daniel Boué, Christopher Pierson, John Breneman, Xiao-Nan Li, Ralph Salloum, David Ashley, Peter de Blank, Eugene Hwang, Sarah Leary, Ashley Plant, Michael Fisher, Susan Chi, Dorothy Crabtree, Mythili Murali, Marla Weetall, Mark Rance, Pius Maliakal, John Baird, Dhiren D’Silva, Kylie O’Keefe, Jeffrey Leonard, Clinton Stewart, Elaine Mardis, Maryam Fouladi, Rachid Drissi
Journal: Neuro-Oncology (2023)

Abstract BMI-1 represents a potential therapeutic target in pediatric HGG given its role in self-renewal and DNA-damage signaling, high expression levels in these tumors, and resultant proliferation blockade, mitotic abnormalities, and radiosensitization when modulated by unesebulin, a microtubule polymerization inhibitor. This phase Ib study sought to determine the recommended phase 2 dose (RP2D) and pharmacokinetic (PK) profiles of unesbulin administered concurrently with radiotherapy and as maintenance therapy in children with newly-diagnosed DIPG or HGG, as well as assess intratumoral PKs and target inhibition within a surgical cohort. As previously reported, the established RP2D from the dose-finding cohort (parts A [capsule] and C [tablet]), consisting of 27 patients (median age: 9 years; 18 with DIPG, 9 with HGG) is 200mg/m2 twice weekly. Eleven additional patients (5 with DIPG, 6 with HGG) have been enrolled in an expansion cohort (part D [tablet]), with no dose-modifying toxicities to date. Among 38 total patients, most common drug-related grade 3/4 adverse effects observed are neutropenia (49%), leukopenia (31%), and elevated ALT (18%). Pharmacokinetic profiles are comparable between capsule and tablet formulations, and corroborate adult data. Genomics correlatives are underway on 13 biopsy and 5 autopsy specimens (2 paired samples). Five patients (median age: 5 years; 4 with DIPG, 1 with HGG) have enrolled in the surgical cohort (part B [tablet]) at the RP2D. PK analyses performed on the first three samples confirm intratumoral unesbulin exposure. In summary, the RP2D of unesbulin at 200mg/m2 twice weekly concurrent with and post-radiotherapy is feasible and well-tolerated, with evidence of blood-brain barrier and tumor penetrance. Survival outcomes as well as ongoing analyses of intratumoral BMI-1 pathway inhibition in surgical cohort samples, plus comprehensive molecular profiling (focusing on BMI-1 and cell cycle signaling) of biopsy and autopsy specimens from the entire cohort, will be shared at time of presentation.
DIPG-01. LIN28B EXPRESSION IN DIFFUSE MIDLINE GLIOMA
Authors: Truman Knowles, Shejuan An, Tina Huang, Jin Qi, Amanda Saratsis
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Diffuse midline glioma (DMG) is the most lethal of all childhood cancers. LIN28B is an RNA binding protein expressed in a variety of cancers, which suppresses the let-7 family of microRNAs, which in turn suppresses a plethora of oncogenes. However, the role of LIN28B in DMG has not yet been explored. Therefore, we sought to determine the pattern of expression and potential function of LIN28B in DMG using rare DMG cell lines. METHODS All studies were performed on DMG cell lines (n=6) and controls (normal human astrocytes n=1, human neural stem cells n=1). RNA-Seq was performed using single-read sequencing at 50bp on the Illumina NextSeq 500 Sequencing System. Cells were then treated with DMSO or the LIN28B inhibitor, LI71, and submitted to functional in vitro studies, as well as RNA-Seq and Western Blot analysis. Functional pathways analysis was subsequently performed on resulting gene expression values with Ingenuity Pathways Analysis (Qiagen). RESULTS Differential LIN28B expression was demonstrated across cell lines, with DMG cells expressing greater LIN28B gene and protein levels compared to controls. LIN28B inhibition with small molecule inhibitor LI71 resulted in decreased cell proliferation and migration, in vitro. A total of 946 differentially expressed genes were identified between treatment groups (FC&amp;gt;2 or &amp;lt;-2, p&amp;lt;0.05). Functional pathways analysis of differentially expressed genes implicated Cancer and Neurological Disease as the top disease processes, with Cellular Movement as the top molecular process in cell lines expressing LIN28B. Further, inactivation of Myc signaling was implicated in cells treated with LI71. CONCLUSIONS Our data demonstrates increased LIN28B expression in DMG cell lines compared with controls, with oncogenic effects on cell proliferation and migration. Further investigation of the LIN28B-let7 signaling axis is warranted in order to further explore LIN28B as a novel therapeutic target in DMG.
TRLS-12. INTRAVENTRICULAR B7-H3 CAR T CELLS FOR DIFFUSE INTRINSIC PONTINE GLIOMA: INTERIM ANALYSIS OF BRAINCHILD-03 ARM C
Authors: Nicholas Vitanza, Rebecca Ronsley, Ashley Wilson, Wenjun Huang, Kristy Seidel, Navin Pinto, Juliane Gust, Rebecca Gardner, Michael Jensen, Julie Park
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND BrainChild-03 is a first-in-human phase 1 clinical trial delivering repeated intraventricular B7-H3 CAR T cells to children with central nervous system (CNS) tumors without lymphodepleting chemotherapy. METHODS We report on the ongoing Arm C for patients with diffuse intrinsic pontine glioma (DIPG), currently enrolling at the highest Dose Regimen (10x10^7 B7-H3CARs/dose). Primary endpoints are feasibility and safety. Secondary endpoints are disease response and correlatives of CAR-T activity. RESULTS 19 patients have enrolled. All had successful CAR-T manufacturing. 17 patients were treated; 13 received sufficient doses for safety evaluation (4 doses/8 weeks) without a dose limiting toxicity (DLT). One patient had a DLT (pontine hemorrhage 8 days post-initial dose). The 5 unevaluable patients include: 2 on protocol not yet evaluable, 2 left the study due to rapid progression, and 1 did not meet eligibility to initiate treatment. Overall, patients have received 134 doses (median: 8/patient, range: 1-36). Adverse events include headache (93%), nausea/vomiting (79%), and fever (57%). Cytokine release syndrome (CRS) or immune effort cell-associated neurotoxicity syndrome (ICANS) have not occurred. Of 14 evaluable patients, 8 enrolled after progression, including some with metastases. Patients with progressive DIPG at enrollment have a median survival of 278 days post-initial dose (3/8 alive). Patients who enrolled before progression have a median overall survival of 207 days (6/6 alive) with 1 patient still receiving protocol therapy after 18 months (36 doses). We have found localized CSF circulating CAR T cells and cytokine elevations supporting local immune activation. CSF mass spectrometry shows modulation of B7-H3 and immune analytes (CD14, CD163, CSF-1, CXCL13). CONCLUSION Repeated intraventricular B7-H3 CAR T dosing has been feasible for children with DIPG, even after progression, with evidence of local immune activation. Tolerability and prolonged stable disease suggest the potential for clinical benefit allowing for future cellular enhancements and combinations.
First-Line, Fixed-Duration Nivolumab Plus Ipilimumab Followed by Nivolumab in Clinically Diverse Patient Populations With Unresectable Stage III or IV Melanoma: CheckMate 401
Authors: Reinhard Dummer, Pippa Corrie, Ralf Gutzmer, Tarek M. Meniawy, Michele Del Vecchio, Céleste Lebbé, Michele Guida, Caroline Dutriaux, Brigitte Dreno, Nicolas Meyer, Pier Francesco Ferrucci, Stéphane Dalle, Muhammad Adnan Khattak, Jean-Jacques Grob, Karen Briscoe, James Larkin, Sandrine Mansard, Thierry Lesimple, Massimo Guidoboni, Silvia Sabatini, Erika Richtig, Rudolf Herbst, Maurice Lobo, Margarita Askelson, Paolo A. Ascierto, Michele Maio
Journal: Journal of Clinical Oncology (2023)

To address the paucity of data in patients with historically poor outcomes, we conducted the single-arm phase IIIb CheckMate 401 study to evaluate the safety and efficacy of nivolumab plus ipilimumab followed by nivolumab monotherapy in clinically diverse patient populations with advanced melanoma.
LGG-19. MULTI-MODALITY CHARACTERIZATION OF PEDIATRIC LOW-GRADE GLIOMA: THE ADDED VALUE OF DIFFERENT DATA MODALITIES
Authors: Debanjan Haldar, Anahita Fathi Kazerooni, Aria Mahtabfar, Nastaran Khalili, Ariana Familiar, Adam Kraya, Meen Chul Kim, Wenxin Tu, Shuvanjan Haldar, Sina Bagheri, Hannah Anderson, Karthik Viswanathan, Ibraheem Shaikh, Jeffrey Ware, Phillip Storm, Arastoo Vossough, Adam Resnick, Ali Nabavizadeh
Journal: Neuro-Oncology (2023)

Abstract Characterization of pediatric low-grade glioma (pLGG) remains a significant challenge in the field of neuro-oncology, with a need for more effective precision diagnostics. Multi-modal analysis, which incorporates data from varied sources, has the potential to provide a comprehensive understanding of the underlying biology of pediatric brain tumors. Despite its potential, the utilization of true multi-modality clustering remains limited in pediatric brain tumor research. In this study, we aimed to address this gap by using a clustering model that incorporated genomics, radiomics, and clinical variables (age, sex, and tumor location) to group patients into distinct clusters. 103 patients with pLGGs were included. Mutations data was derived from whole genome sequencing obtained through the PedCBioportal. Radiomic data was obtained from MR imaging through the Children’s Brain Tumor Network and included features from pre- and post-contrast T1, T2, FLAIR, and ADC sequences. Categorical variables included sex (male vs female), genetic mutation status for 10 selected genes (BRAF, FGFR1, TSC1, TSC2, NF1, MYB, EGFR, ALK, IDH1, and RB1) that are known to play a role in the pathogenesis of pLGG (mutated vs non-mutated), and tumor location (9 categories). Continuous variables included age (days) and radiomic features. All numerical variables were normalized and reduced into principal components that captured 90% of the variance in the data prior to clustering. Various clustering iterations were performed incorporating combinations of radiomic, genomic, and clinical data. Our models identified two distinct clusters and the PFS differences between clusters approached statistical significance with the integration of information from all modalities when compared to any combination of subsets of data, highlighting the complementary value of these modalities in providing a comprehensive characterization of pLGG. This study provides preliminary evidence for the utility of multi-modality data clustering in improving our understanding of pLGG and supports further investigation into this approach.
TRLS-15. TARGETED THERAPY IN PEDIATRIC CNS TUMORS - A SINGLE INSTITUTION EXPERIENCE
Authors: Braden Olsen, Keishla Gonzalez, Angela Parra del Riego, Marleni Torres, Camila Pabon, Ossama Maher, Toba Niazi, John Ragheb, Matthew Hall, Ziad Khatib
Journal: Neuro-Oncology (2023)

Abstract Primary central nervous system malignancy treatment remains a difficult problem despite advancement in techniques. Personalized medicine is evolving in making treatment decisions and particular molecular characteristics allow new targeted therapies to be specific and effective. We retrospectively present patients with primary CNS tumors receiving targeted therapy from 2016 to the present date. Outcomes included length of therapy, time until progression of disease, and overall response. Our study includes 32 patients with malignancies such as Astrocytoma, Ganglioglioma, Glioblastoma, and Diffuse Intrinsic Pontine Glioma (DIPG), among others. Analysis was based on patients’ underlying malignancy and included variables such as identified mutations, targeted therapy, progression vs resolution of disease, and time to progression of disease after initiation of targeted therapy. Overall results show 23 patients with at least 1-year-survival. The most common targeted therapy was Trametinib, treating tumors of glial origin. 14 patients showed no progression after starting targeted therapy, the majority low grade Gliomas and Medulloblastomas. Multiple mutations were found with the most frequent being BRAF. Of our 11 patients with BRAF mutations, 8 had no progression of disease after starting Trametinib or Dabrafenib. Patients with Atypical Teratoid Rhabdoid Tumors (ATRT) were treated with either Alisertib or Alisertib/Tazemetostat and 2 out of 4, both treated with Alisertib maintenance therapy, had no disease progression after targeted therapy. Best outcomes with no disease progression were primarily Gliomas, treated with Trametinib, and Medulloblastomas, treated with Vismodegib. Of our patients with DIPG, treated with Ribociclib, average time to disease progression on targeted therapy was 4.7 months and survival rate was 33%. We have shown excellent use of targeted therapy and our analysis highlights the need for continued exploration of targeted therapy among patients with CNS tumors.
MDB-15. CLINICAL CHARACTERISTICS AND OUTCOME OF CHILDHOOD LI-FRAUMENI SYNDROME MEDULLOBLASTOMA PATIENTS
Authors: Anna Kolodziejczak, Lea Guerrini-Rousseau, Julien Masliah Planchon, Martin Mynarek, Martin Sill, Robert Autry, Eric Zhao, Steffen Hirsch, Christelle Dufour, Olivier Ayrault, Sebastian Waszak, Vijay Ramaswamy, Virve Pentikainen, Steven Clifford, Ed Schwalbe, Luca Massimi, Matija Snuderl, Matthias Karajannis, Christine White, Shelagh Redmond, Loizou Loizos, Marcus Jakob, Irene Schmid, Julia Hauer, Claudia Blattmann, Maria Filippidou, Christian Sutter, Torsten Pietsch, Stephan Frank, Denis Schewe, David Malkin, Astrid Sehested, Tai-Tong Wong, Fernando Carceller, Sabine Mueller, Michael Taylor, Uri Tabori, Eric Bouffet, Marcel Kool, Felix Sahm, Christian Kratz, Dominik Sturm, David Jones, Stefan Rutkowski, Olaf Witt, Gaëlle Bougeard, Kristian Pajtler, Stefan Pfister, Franck Bourdeaut, Till Milde
Journal: Neuro-Oncology (2023)

Abstract Patients with Li-Fraumeni syndrome (LFS) who develop medulloblastoma (MB) have a very poor prognosis. The development of novel therapeutic strategies is challenged by the lack of clinical data for this patient group. We here present clinical and molecular data on a retrospective cohort of pediatric patients with LFS-associated MB. This is an international, retrospective, multicenter cohort study. Patients with LFS-associated MB under 21 years and class 5 (pathogenic) or class 4 (likely pathogenic) constitutional TP53 variants were included. We evaluated TP53 mutation status (constitutional and somatic), DNA methylation subgroup, treatment modalities, event-free (EFS) and overall survival (OS), patterns of recurrence, as well as occurrence of secondary neoplasms. Forty-seven individuals with LFS-associated MB were included. MBs were classified mainly as Sonic Hedgehog (SHH) group (87%). TP53 variants were classified as class 5 (70%) and class 4 (30%). The majority (74%) of TP53 variants represented missense variants. The 2-year (y-) EFS and -OS were 33% and 53%, respectively. A significantly better outcome was seen in patients who received post-operative radiotherapy (RT) (2y-EFS: 44%, 2y-OS: 60%) or chemotherapy before RT (2y-EFS: 24%, 2y-OS: 48%) compared with patients who received no RT (2y-EFS: n.a., 2y-OS: 25%). No significantly different outcomes were seen between patients treated either according to protocols including high-intensity chemotherapy or receiving only maintenance-type chemotherapy (2y-EFS: 42% and 31%, 2y-OS: 68% and 53%, respectively). Patients with LFS-associated MB have a dismal prognosis. Use of RT in LFS-associated MB significantly increased survival rates in the presented cohort, but choice of chemotherapy regimen did not influence their clinical outcome. To improve the outcome of patients with LFS-associated MB, prospective collection of clinical data and development of novel treatments are required.
IMMU-02. CMV-EXPANDED T-CELLS IN GLIOBLASTOMA PATIENTS: TRANSLATIONAL RESEARCH
Authors: Linde F C Kampers, Golnaz Rajabpour, Michael Bitar, Volker Schirrmacher, Wilfried Stücker, Stefaan W Van Gool
Journal: Neuro-Oncology (2023)

Abstract Human cytomegalovirus (CMV) is a contributing factor to tumour expansion and progression in glioblastoma patients. Patient-derived non-modified CMV-specific T cells can be isolated, ex vivo re-stimulated with CMV and expanded before IV infusion. Adoptive T cell Therapy with expanded CMV-specific T cells and has been shown to improve GBM prognosis. We aimed to develop a CMV-specific T cell expansion protocol. PBMCs were isolated from blood of 12 healthy CMV-antibody positive donors and 9 patients (three glioblastoma patients, four prostate cancer patients, one pancreatic cancer and one rectal cancer patient). CMV-pulsed stimulating and responding PBMC (S:R ratio = 1:2) were cultured in RPMI supplemented with IL-21 and subsequent IL-2 addition for 9 days. Cell quality was ensured via cell surface staining and intracellular cytokine assays. Product sterility was tested with aerobic and anaerobic sterility assays, Endotoxin test and mycoplasma tests. Autologous CMV-specific T cells were successfully isolated from CMV positive donors and cancer patients. Ex vivo analysis of CMV-specific T cells after in vitro CMV restimulation and expansion resulted in 6.81 x 106 to 2.52 x 108 viable cells (Δ1.09 x 108 with Δ90% viability) with antigen-specific active T-cell frequencies ranging from 15.10% to 41.98% (median 38.39%) in healthy donors and 14.78% to 54.75% of total CD8+ T cells (median 31.42%) in cancer patients. A cell culture protocol was developed to expand autologous CMV-specific CD8+ T cells from patients. Product release criteria were defined as 1-2 x 107 cells per m2 body surface area with a &amp;gt;50% viability rate and &amp;gt;15% CMV-specific CD8+ T cells within the total T cell population. The translation of the cell culture protocol within a GMP setting is envisioned. The efficacy of such treatment has to be elaborated once the cell product is approved for medicinal use.
XRT-05. LITHIUM PREVENTS RADIATION-INDUCED HIPPOCAMPAL MICROGLIA SENESCENCE IN A MOUSE MODEL OF PEDIATRIC CRANIAL RADIOTHERAPY
Authors: Carlos Rodrigues, Efthalia Preka, Alejandro Lastra-Romero, Georgios Alkis Zisiadis, Christodoulos Zisiadis, Adamantia Fragkopoulou, Klas Blomgren
Journal: Neuro-Oncology (2023)

Abstract Radiotherapy is essential in the treatment of high-grade brain tumors. While often lifesaving, it typically results in long-term complications in 50-96 % of the treated individuals, where cognitive deficits are particularly debilitating, especially in pediatric patients. Although the survival rates have improved dramatically, there are currently no treatments or preventive strategies available to ameliorate the late cognitive complications. Lithium (Li), long used to treat patients with bipolar affective disorders, has been shown to reduce irradiation-induced cognitive deficits in rodent models by preventing apoptosis of the neuronal stem and progenitor cells in the hippocampus and stimulating their division. However, except for these anti-apoptotic and pro-neurogenic effects, there is limited understanding of how Li exerts its actions in the brain. This work aimed to further elucidate the mechanisms behind the protective action of Li in the irradiated young brain. To this end, post-natal day (PD) 21 C57BL6/J mice were intraperitoneally injected with lithium chloride (4 mmol/kg) and subsequently kept on a Li carbonate diet for 4 weeks. Control animals were injected with saline and administered an equivalent control diet. At PD25, the animals were subjected to a single dose of 8 Gy whole brain irradiation, and 6 weeks after irradiation, they were sacrificed, and their hippocampi were harvested for single-cell RNA sequencing and RT-qPCR. The attained results showed that irradiation induced hippocampal microglia senescence, as judged by the increased expression of the senescence-associated genes Cdkn1a, Cdkn2, Ccl12, C/Ebp and others in this cellular population. Conversely, Li prevented microglia senescence by activating the Bcl2 family of genes, as confirmed by the lower expression of the abovementioned senescence-associated genes in the Li-treated animals. These results provide the first step towards understanding the action of Li in the brain and confirm its potential to become the first pharmacological treatment for irradiation-induced late cognitive effects.
IMG-01. LONGITUDINAL FMRI OF VISUAL, AUDITORY AND MOTOR FUNCTION IN PEDIATRIC CRANIOPHARYNGIOMA AFTER TREATMENT WITH PROTON RADIOTHERAPY
Authors: Ping Zou, ChiaHo Hua, Jinsoo Uh, Heather Conklin, Thomas Merchant, Ranganatha Sitaram
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Craniopharyngioma accounts for approximately 4% of childhood central nervous system tumors and has a 5-year overall survival rate exceeding 90%. Survivors of childhood craniopharyngioma may experience neurologic sequalae, including visual and fine motor deficits, and subclinical hearing loss associated with tumor and treatment. Contemporary treatment includes radical surgery or more limited surgery and proton radiotherapy (PRT). Here we report on a longitudinal fMRI study probing visual, auditory, and motor function in pediatric craniopharyngioma patients. METHOD: The study (NCT01419067) was IRB approved and informed consent was obtained for each patient. Functional MR images were acquired at 4 time points: after surgery and before PRT (TP1), and 18-months (TP2), 36-months (TP3), and 60-months (TP4) after PRT. Data from a sensory survey fMRI task (visual: flashing checkerboard; auditory: dissonant ascending/descending pure tones; and sensory/motor: button pushing when stimuli were on) for 67 patients were analyzed at the 4 time points. The median age was 11.7 years (range 8.3-20.2 years) and the female/male ratio was 37/30. RESULTS Significant brain activation was seen in visual cortices, auditory cortices, and supplementary motor area (SMA) and motor cortices for all 4 time points. Over the time, visual and motor cortices showed minimum changes in activation; however, there was a small increase in SMA. For the auditory cortices, the activation volume in Heschl’s gyri increased bilaterally, and the lateralization index decreased (TP1: 70%; TP2: 46%; TP3: 39%; and TP4: 26%) due to larger increases in the right Heschl’s gyrus. CONCLUSION Increasing activation in Heschl’s gyri, especially on the right side, after PRT suggests decreasing efficiency in distinguishing tones in these patients. These findings may be associated with late effects involving the specific gyri or neuropathways affected by surgery or irradiation.